Project summary. Considerable progress has been made to improve our understanding of the genetic basis of cancer and the mechanisms of oncogenesis. In spite of this, even for widely studied human cancers such as diffuse large B cell lymphoma (DLBCL) causative factors remain elusive. This is due, at least in part, to the extensive genetic heterogeneity of most human populations. In contrast, domestic dogs are organized into more than 350 phenotypically distinct genetic isolates ('breeds') characterized by unique constellations of morphology, behavior, and susceptibility to specific diseases including DLBCL. Humans and dogs share similar physiology, extensive genome homology and are exposed to the same environment. We have shown that the incidence and lifetime risk of naturally occurring canine DLBCL (cDLBCL) differ markedly between breeds and that cytogenetic changes associated with hematopoetic tumors are evolutionary conserved between human and dog. Significantly, we have also identified chromosome aberrations in dogs for which corresponding changes have not yet been reported in humans. Combined with the recent advances in canine genomics resources, these unique features of dog population structure strongly support the role of the dog an ideal model system to identify genes that define diagnosis, prognosis and risk for DLBCL. Using molecular cytogenetics and genome-wide association studies of cDLBCL, we will identify cancer-associated genes that continue to evade detection through comparable studies of human DLBCL. Project relevance: DLBCL is a major cause of human death. Almost 50% of DLBCL patients receiving therapy do not survive more than five years, indicating that the 'disease1 requires further classification and that we need to understand more about the genetic basis of this cancer. We propose that key genes associated with DLBCL continue to remain elusive and undetected in studies of human patients due to the high level of genetic variability in human populations. The structure of purebred dog populations makes them an ideal model for gene discovery. We will investigate chromosome changes associated with canine DLBCL in highly susceptible dog breeds as a means to identify such genes. We propose that Man's best friend will provide the keys to unlocking some of nature's most intriguing puzzles about cancer.